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Epigenetic Therapeutics: Mechanisms, Modalities and Outcomes for Human Health Marc Muskavitch Sr. Director, Epigenetics September 10, 2014
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2. Epigenetic Therapeutics Epigenetics (“over” or “upon” - genetics) is the study of (heritable) changes in gene function that depend on mechanisms other than changes in DNA sequence Consensus 2013 “an epigenetic trait is a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence” Berger et al., 2008 “the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms” Holliday, 1990 ‘‘the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being” Waddington, 1942
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3. Epigenetic Therapeutics RNA Biology Long Noncoding RNAs Micro RNAs RNA Editing Chromatin Biology Histone Writers/Erasers Histone Readers/Remodelers DNA Methylation Wahlestedt Nat Rev Drug Disc 2013Arrowsmith et al Nat Rev Drug Disc 2012
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4. Epigenetic Therapeutics Epigenetics and disease Mutations in genes encoding epigenetic modifiers (e.g., HDAC, HAT, DNMT, MECP) and ncRNAs are associated with human disease Antagonists of histone deacetylases are moving into the clinic Anti-sense RNA-based therapies are moving into the clinic Ensemble therapeutics Epigenetic therapeutics can be considered “ensemble therapeutics” because drugs directed against an epigenetic function will affect the expression/function of multiple targets Chromatin writers/erasers/readers interact with multiple sites Antisense RNAs target multiple mRNAs and/or ncRNAs
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5. Epigenetic Therapeutics Histones and DNA are modified by a variety of enzymes HAT: histone acetyl transferase HDAC: histone deacetylase HMT (KMT): histone methyltransferase HDM (KDM): histone demethylase DNMT: DNA methyltransferase Peterson and Laniel Curr Biol 2004 Yandell The Scientist 2014
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6. Epigenetic Therapeutics Open (active/transcribed) and closed (inactive/ nontranscribed) configurations of chromatin Klug et al 2011
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7. Epigenetic Therapeutics Klug et al 2011 miRNA regulation and RNA interference lead to targeted RNA degradation microRNA (miRNA) precursors are transcribed in the nucleus, then processed into mature miRNAs by Dicer miRNAs bind to the RNA-induced silencing complex (RISC) and catalyze degradation of messenger RNAs and noncoding RNAs
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8. Epigenetic Therapeutics Klug et al 2011 Dicer cleaves double-strand RNA (including double-strand RNA viruses) into 21 nucleotide fragments These 21 nt silencing RNAs (siRNAs) bind to the multicomponent RISC RISC targets for degradation messenger RNAs and noncoding RNAs, complementary to the bound siRNA Anti-viral defense system
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9. Diseases associated with mutations in epigenetic modifiers Gos Acta Neurobiol Exp 2013
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10. Epigenetic Therapeutics Chromatin Biology Histone Writers/Erasers Histone Readers/Remodelers DNA Methylation Arrowsmith et al Nat Rev Drug Disc 2012
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11. Arrowsmith et al Nat Rev Drug Disc 2012 HDAC and sirtuin inhibitors in clinical development
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12. Long noncoding RNAs implicated in human disease Wahlestedt Nat Rev Drug Disc 2013
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13. Epigenetic Therapeutics RNA Biology Long Noncoding RNAs Micro RNAs RNA Editing Wahlestedt Nat Rev Drug Disc 2013
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14. Anti-sense RNA therapeutic pipeline at Isis Pharmaceuticals http://www.isispharm.com/Pipeline/index.htm
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15. Epigenetic Therapeutics
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16. Epigenetic Therapeutics Modalities for epigenetic therapies Small molecules: antagonists and agonists of epigenetic modifiers (oral, subcutaneous, intravenous) Biologics (antibodies, factors): inhibitors or substitutes for epigenetic modifiers (oral, subcutaneous, intravenous) Antisense oligonucleotides (ASOs): reduction of RNA levels by RNA interference (subcutaneous, intravenous, intrathecal) Cell and gene therapy: genome editing (ZFN, TALEN, CRISPR), antisense, noncoding or coding RNA delivery (viral vectors)
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17. Epigenetic Therapeutics Company TargetIndicationMolecule/ IDStatus Acetylon Pharmaceuticals HDAC6Lymphoma, Multiple MyelomaACY-1215Phase I/II Constellation EZH2 BET Lymphoma SM CPI-0610 Preclinical Phase I Epizyme DOT1L EZH2 Leukemia NHL EPZ-5676 EPZ-6438 Phase I/II Phase I/II BCL GlaxoSmithKline LSD1 BET SCLC, Leukemia Cancer GSK2879552 GSK525762 Phase I Eisai (with Epizyme) EZH2BCLE7438Phase I/II Salarius LSD1Ewing’s SarcomaSP-2528Preclinical Zenith Pharmaceuticals BETHematologic CancersZEN-3365Preclinical Drug development pipeline (in part)
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18. Epigenetic Therapeutics HDACi approved by FDA for clinical use Vorinostat Cutaneous T cell lymphoma (Merck) Romedepsin Cutaneous T cell lymphoma (Gloucester Pharmaceuticals) Belinostat Peripheral T cell lymphoma (Spectrum Pharmaceuticals) HDACi side effects/liabilities Fatigue Nausea/diarrhea Thrombocytopenia Cardiotoxicity (prolonged QT interval, hERG effects)
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19. HDAC6-selective inhibitor in clinical trials Ricolinostat (Acetylon Pharmaceuticals) Indications Multiple myeloma With bortezomib or lenalidomide, and dexamethasone Relapsed-and-refractory multiple myeloma With pomalidomide and dexamethasone Relapsed/refractory lymphoid malignancies Epigenetic Therapeutics
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20. Epigenetic Therapeutics DNMTi approved by FDA for clinical use Azacitidine (Pharmion Corporation) Decitabine (InnoPharma) Myelodysplastic syndrome DNMTi side effects/liabilities Neutropenia Thrombocytopenia Anemia Pneumonia Fatigue
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21. Epigenetic Therapeutics ASOs approved by FDA for clinical use Mipomersen (ApoB) (Isis Pharmaceuticals/Genzyme) Familial hypercholesterolemia Fomivirsen (Isis Pharmaceuticals/Ciba Vision Corporation) Cytomegalovirus retinitis ASO side effects/liabilities Prolonged activated partial thromboplastin time (aPTT) Activation of alternative complement pathway Pro-inflammatory reactions Elevation of hepatic enzymes (ALT, AST)
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22. Epigenetic Therapeutics Common drugs with known/possible epigenetic impacts Csoka and Szyf Med Hypoth 2009
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23. Epigenetic Therapeutics Epigenetic drugs and pregnancy/breastfeeding Should epigenetic therapeutics be avoided during conception, pregnancy and breastfeeding? For vorinostat, romedepsin, belinostat: US FDA Pregnancy Category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Csoka and Szyf Med Hypoth 2009
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24. Epigenetic Therapeutics RNA Biology Long Noncoding RNAs Micro RNAs RNA Editing Chromatin Biology Histone Writers/Erasers Histone Readers/Remodelers DNA Methylation Wahlestedt Nat Rev Drug Disc 2013Arrowsmith et al Nat Rev Drug Disc 2012
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25. Epigenetic Therapeutics Epigenetics and disease Mutations in genes encoding epigenetic modifiers (e.g., HDAC, HAT, DNMT, MECP) and ncRNAs are associated with human disease Antagonists of histone deacetylases are moving into the clinic Anti-sense RNA-based therapies are moving into the clinic Ensemble therapeutics Epigenetic therapeutics can be considered “ensemble therapeutics” because drugs directed against an epigenetic function will affect the expression/function of multiple targets Chromatin writers/erasers/readers interact with multiple sites Antisense RNAs target multiple mRNAs and/or ncRNAs
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Epigenetic Therapeutics: Mechanisms, Modalities and Outcomes for Human Health Marc Muskavitch Sr. Director, Epigenetics September 10, 2014
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